@article {Ribeiro2022.03.31.486558, author = {Marcelo Lima Ribeiro and N{\'u}ria Profit{\'o}s-Pelej{\`a} and Juliana Carvalho Santos and Pedro Blecua and Diana Reyes Garau and Marc Armengol and Miranda Fern{\'a}ndez-Serrano and Hari P. Miskin and Francesc Bosch and Manel Esteller and Emmanuel Normant and Gael Rou{\'e}}, title = {GPR183 mediates the capacity of the novel CD47-CD19 bispecific antibody TG-1801 to heighten ublituximab-umbralisib (U2) anti-lymphoma activity}, elocation-id = {2022.03.31.486558}, year = {2022}, doi = {10.1101/2022.03.31.486558}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Targeted therapies have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decade; however, most subtypes remain incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory B-NHL patients either as a single-agent or in combination with ublituximab, a CD20 antibody, which is also being combined with the PI3Kδ/CK1e inhibitor, umbralisib ({\textquotedblleft}U2{\textquotedblright}-regimen). In this study, we demonstrated that TG-1801 potentiates ublituximab-mediated antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP), leading to an additive anti-tumour effect of the TG-1801/U2 combination in B-NHL co-cultures. Accordingly, in a B-NHL xenotransplant model, the triplet achieved a 93\% tumour growth inhibition, with 40\% of the animals remaining tumour-free 35 days after the last dosing. Transcriptomic analysis further uncovered the upregulation of the G protein-coupled receptor, GPR183, as a crucial event associated with TG-1801/U2 synergism, while pharmacological blockade or genetic depletion of this factor impaired ADCP initiation, as well as cytoskeleton remodelling and cell migration, in B-NHL cultures exposed to the drug combination. Thus, our results set the preclinical rationale and support a combination strategy of TG-1801 with PI3Kδ- and CD20-targeting agents in patients with B-NHL.Competing Interest StatementH. Miskin reports personal fees from TG Therapeutics, Inc. during the conduct of the study. E. Normant reports employment and ownership of stock with TG Therapeutics. G. Rou{\'e} reports grants from TG Therapeutics and Instituto de Salud Carlos III during the conduct of the study. The remaining authors have no competing financial interests.}, URL = {https://www.biorxiv.org/content/early/2022/04/01/2022.03.31.486558}, eprint = {https://www.biorxiv.org/content/early/2022/04/01/2022.03.31.486558.full.pdf}, journal = {bioRxiv} }